Today is our great privilege to have Ionis as part of our RBC 2024 Global Healthcare Conference. Representing the company, we have Beth Hougen, Chief Financial Officer, as well as Wade Walke, Head of IR. Beth and Wade, thanks so much for joining us. How are you guys doing?
Great. Thanks for having us.
Super, super.
Good to be here.
I do have a long list of questions here, but maybe before we go into the individual programs, it would be great, Beth, if you can give us a little bit of an overview of what progress has the organization made over the last few months and maybe most importantly, what's ahead here for Ionis.
Sure. Happy to. It's just been a great start to the year. A lot of momentum going into the year. We now have our first Ionis co-branded, co-commercialized medicine, WAINUA, on the market for ATTR polyneuropathy patients, and the launch is going well. We're looking forward to additional approvals in other geographies, so we expect that to continue. We're also really excited about bringing more medicines to patients with olezarsen and donidalorsen, just increasing the Ionis discovered and developed medicines that'll be reaching patients over the coming months and years. So we're excited about all of that. We've got the NDA for olezarsen in FCS has been submitted now, so we're waiting for FDA feedback that it's been accepted, and we hope for priority review with that. And if we get priority review, we'll have that drug hopefully approved and on the market late this year.
Following very shortly behind that is donidalorsen. We had positive phase 3 data from that drug earlier this year, and we're in the process of getting ready to file the NDA or submit the NDA with the FDA on that drug. So again, another launch potentially next year with that drug. With olezarsen, our severe high triglyceride broad patient population indication is fully enrolled in two out of three studies, so that's moving along well. Not to forget the mid-stage pipeline. The mid-stage pipeline has performed. We had positive DGAT2 data in MASH just recently, and we anticipate additional data readouts in that pipeline over the course of this year. We continue all that into next year as well.
It's a great time right now as we get ready to launch multiple drugs and bring a steady cadence of drugs to the market for these patients.
That's a great overview. Maybe if I may, on WAINUA, maybe on the TTR cardiomyopathy space more broadly, obviously HELIOS-B is going to be a very important catalyst for biotech more broadly in 2024. So maybe walk us through what are your expectations for that dataset and how you're thinking about base case scenario, worst case scenario, and upside scenario for Ionis into that data.
Yeah. It's a great question. It's a question that you can imagine there's a lot of focus on that right now across the space. We are running, as you know, the largest cardiomyopathy study with over 1,400 patients. It's fully enrolled, and we anticipate data in 2025 if we have an early readout or more likely a 2026 readout so that we can take the study all the way to its natural conclusion, which will be very important for ensuring that we have a very robust dataset coming from that study. As we think about HELIOS-B, we're really looking forward to the first silencer reading out in this space. I think we're all going to learn a lot when that happens.
For Ionis, frankly, we really see a positive read-through in almost any scenario in that readout, given the strength of the profile WAINUA has demonstrated in polyneuropathy, the efficacy we've seen, the safety we've seen, the self-administration with an autoinjector administration profile, and just the robustness of the dataset that we can have with cardiomyopathy. We really see almost no scenario in which this won't be positive for Ionis. If they miss, we anticipate our data will be our study is so much bigger that it'll be positive. If they just meet their endpoint, we think we'll be able to do at least as well. And if they hit it out of the park, then that's great. We would anticipate a similar outcome for CARDIO-TTRansform and WAINUA. So you want to add?
Yeah. I'd say the exciting thing is that silencers as a class look very interesting to us because we've already seen early signs that there's benefit for using silencers in cardiomyopathy patients. We've seen with our first-generation drug in an investigator-initiated study by Merrill Benson that followed patients with cardiomyopathy over years that there were signs of benefit in those patients. Now, obviously, it's a small study, but still, the movement was positive in multiple measures of cardiac function and imaging. And then we've seen some analysis from our NEURO-TTRansform study, the NEURO-TTRansform study, that shows that in patients that also had polyneuropathy and cardiomyopathy, that there was improvement in cardiac function as well. So there's definitely signs that silencers as a class will show benefit in these patients.
And so, as Beth said, any sign of positive news from the HELIOS-B study reads very positive for us.
Got it. Very helpful. Maybe Wade, if I can push, what are your expectations for the combination? Do you think the silencers and stabilizers will show a synergistic effect? In other words, do you think that the Alnylam trial is going to hit on both the overall population, or do you think that that trial is going to hit only in the monotherapy arm?
I think of anybody out there, we're best positioned to answer that question because really nobody knows right now, right? But with a study the size of our study, with as many patients as we have, both naïve to tafamidis and on top of tafamidis, we have probably the best potential to show if there is a benefit in combination use, right? The fact that you're getting rid of 80%-90% of the TTR protein means there's not a lot of TTR protein left to stabilize. So then the question is, do you get most of the benefit from getting rid of most of the protein? Is there any benefit left from stabilizing the remaining amount? Possibly. So that's a question.
I think it's really hard to say right now what the benefit is in combination, but I think we'll be able to at least have the best possibility of answering that question with our study.
Got it. Super helpful. Probably I am pushing my luck, but I'll try. In a scenario where there's no effect at all as add-on to tafamidis, do you still have optionality to tweak your trial and potentially do something similar to what Alnylam did, which is essentially dichotomize the primary endpoint between the overall population and the monotherapy? Is that something that is still possible in your trial, or any thoughts on that maybe? Go ahead, Beth.
Sure. So it is still possible. One of the things we're watching our study very carefully. We're watching the event rates very carefully. We're watching the types of events very carefully. And we're going to be paying very close attention to the upcoming readout for HELIOS-B. And based on all of those data points, we'll be able to make decisions about what we do, if anything, going forward. So none of that is off the table today. We don't have any specific plans at this point in time to make any changes. We don't see any need. But again, all of these data are coming to bear. We'll pay very close attention to all of that.
Our goal is to ensure that this study is as successful as it possibly can be, and not just today for regulatory purposes and getting the drug approved, but more importantly, to ensure success in this very, very large and growing market. This is a $10+ billion market, and we want to make sure that we're able to capture a substantial amount of that market, that we can be the silencer of choice for these patients. We believe WAINUA is positioned to do that, and the study and the data from the study is going to support that. So we want to give it all the possible opportunity for success that we possibly can.
Got it. Got it. Maybe last one on this one, and I promise I'll move on. I believe at this point of the trial, that's when you're supposed to see kind of an acceleration of the events, right? This is where you're getting to the hockey stick portion of the trial. What can you tell us about the blinded event rate in your trial, and whether or not you're seeing an acceleration of events and if that acceleration is on track with your expectations?
Yeah. So we can't tell you a lot of information about what we're seeing. Say that it is tracking according to our expectations, and you're right, in an outcome study, you do tend to get an accumulation of events as you get towards the end of the study. And so that's about all the color I can give you, but it is tracking according to our expectations, which we think is a good thing.
All right. Great. Maybe a few minutes into TTR polyneuropathy. You guys already mentioned WAINUA. Obviously, congrats on the approval and the great label, super clean, no thrombocytopenia, none of the liabilities that the prior technology has had. $5 million in the very first quarter. Is that on par with your expectations, number one? Then two, are there any leading indicators on how the launch is going in Q2? Any initial thoughts on how the launch is tracking?
Sure. Yeah. We thought that Q1, given that we launched it, sort of had a partial quarter, if you will. So Q1, we were pleased with the launch. Importantly, we saw switches. We saw naïve patients. We saw prescriptions coming from a variety of different specialties. And all of that, I think, gives us real confidence that WAINUA's profile, again, safety, efficacy, and dose administration is being well received. And interestingly, we're also seeing uptake on payers, and that's, I think, a really important aspect of the launch. Oftentimes, it takes a little bit to get that uplift, if you will, with the payers, but we're seeing reimbursement going very well. So I'd say all of the launch metrics are trending the way we would expect.
I can't give you a lot of detail, but I can tell you that everything that we're seeing right now supports the fact that WAINUA is launching very strongly, and we would expect that to continue.
Got it. Got it. Very helpful. Where do you think this product can go ultimately? I mean, Alnylam is doing $1 billion in revenues. TTR polyneuropathy is first to market. Where do you think your product can peak at as second to market in relatively small indications compared to TTR cardiomyopathy like TTR polyneuropathy?
So I think what's important to remember is that there's about 40,000 patients with polyneuropathy, and that includes mixed phenotype patients who have polyneuropathy symptoms as well as the cardiomyopathy symptoms. And of those 40,000 patients, less than 80% or actually, more than 80% of those patients are not treated with an approved therapy today. So think about that. That's a huge market opportunity to grow this market. So with less than 20% of patients actually on an approved therapy, there's tremendous room for more therapies like WAINUA, and we think that's really where our and AstraZeneca's focus is. We love the switch patients. We'll take them all day, but we really are focused our marketing efforts and our sales efforts on that more than 80% of patients who don't have a treatment today, finding those patients, getting them diagnosed, shortening that journey to diagnosis.
These patients have miserable, miserable symptoms. It's a fatal disease, and it takes years in many specialties before they are actually diagnosed. That's where our focus is. So we think there's tremendous opportunity for a substantial market for WAINUA with those patients, so.
Okay. Okay. That's helpful. Maybe pivoting to hereditary angioedema, obviously, going to see data later this month. Can you maybe just give us a little bit of data preview and how should we think about that dataset? And importantly, how should we think about the Q4W versus the Q8W? I think the Q4W have shown 90% reduction in phase 2. How should we think about 80% or more like 60%-70%? How should we think about that part?
So we reported positive data in January from our phase 3 HAE study for donidalorsen, and we were very pleased by the fact that we got 3 late-breaking oral presentations at the EAACI meeting here at the end of the month. And that was a bit of a pleasant surprise for us to have 3 presentations on the same drug, ones on the phase 3 data, ones on the phase 3 OLE data, and the third one is on the switch study data. And so we're pretty excited about being able to really show the extent of how this drug works, not only in phase 3, but what it looks like in the long term, like at baseline, what they look like after coming into the study and being on treatment with donidalorsen. And then what's their preference?
At the end of the study, they're asked whether they prefer the previous treatment or donidalorsen and the reasons why they preferred it. And so we think that the exciting thing about donidalorsen is that it has all of these different aspects that patients are looking for in one treatment. Patients are looking for efficacy, right? And so a lot of patients take Takhzyro because it has the best efficacy out there right now, right? But it also has a fairly onerous treatment paradigm, right? You've got to take—most patients have to take it every two weeks. It's a large volume injection, and many patients describe it as pretty painful. So a lot of patients tried. Convenient. You could take it as an oral daily pill. Definitely not as efficacious.
Also has some GI side effects, but they were looking for something different, right, because Takhzyro didn't have everything that they wanted in it. Donidalorsen has the ability to basically take a small volume autoinjector, self-administered product every four weeks or every eight weeks. And with good efficacy, safety and tolerability, we've seen is good so far. All of these things in a single product is something that we think patients and physicians are really looking for. And that's one of the things that we're excited about this product. And that's one of the things I think we'll be able to show you at the EAACI meeting and on our webcast that's associated with that on May 31st, that we have this really exciting.
It's really a first of its kind study. None of the other treatments that are on the market today have done anything similar to this. It really clearly will demonstrate why patients find donidalorsen a treatment of choice. You'll be able to see how easy it is to move patients from one treatment to donidalorsen. That'll be helpful for patients. It'll give them peace of mind. It'll be helpful for their physicians as well. But it'll also be really helpful for payers in that it will help payers understand that you don't have to be on two treatments for long periods of time in order to be able to switch effectively and safely. Really important part of the data that you're going to see at EAACI here in a couple of weeks, so.
If I could push, is Q8W nice to have or a must-have for differentiation?
Well, I mean, we're going to file for both those paradigms. And for us, we see it as kind of evolving the treatment strategy. Right now, to get your best efficacy, you've got to. Some can take it every 4 weeks, right? We can have a drug that you can take every 4 weeks, which is already much better. And then if you want to and you can tolerate or I shouldn't say tolerate, but you can move to every 8 week and still have the attack-free profile using every 8 week, then that gives you that option, right? And so it's going from 2-week to 4-week to 4-week to 8-week dosing, right? And we think that that's a really attractive profile to have because there may be a lot of patients that can take that every 8-week dosing and be just fine.
Got it. Got it. Helpful. Maybe circling back on APOC3, you mentioned you filed in April. Obviously, the dataset was pretty uncontroversial, actually pretty impressive with 11 pancreatitis and placebo versus one pancreatitis in each of the active arms. Is there anything that keeps you up at night, or how should we think about that? And what's go-no-go decision for priority review versus standard review here?
I would say there's nothing keeping us up at night. We are exactly where we need to be to get ready to launch this drug. The last step is really to bring our field team on board, and we'll be doing that over the next couple of months. The submission to the FDA went very smoothly. We were able to get that submitted very quickly, and we're just waiting to hear from them. Really, what's the go-no-go on priority review versus standard review is really dependent on the FDA. It's a very important medicine for patients who don't have anything else right now. So there's a very serious need for a treatment. There aren't any in the United States. I think we also part of that consideration is we have breakthrough therapy designation and orphan drug designation.
So all of that plays into our belief that this will be priority review. If it is priority review, we anticipate a PDUFA date in December, and we'll be able to, if approved, launch right away after that as well. So nothing keeping us up at night. We're excited to go. We're looking forward to our first independent launch, actually.
Maybe in that context, since this will be your first launch solo, maybe just can you remind us how you're thinking about the size of the salesforce, how many salespeople, back-office people, MSL people you anticipate to have? Maybe in the context of how should we think about the SG&A uptick in that context?
Yep. So a lot of the functions from a commercial and medical affairs perspective are already on board at Ionis. We've had our medical affairs team in the field for quite some time already. So most of the build, if you will, has happened already. We did bring our national sales director on board very recently. He's going to be building out his team with his regional directors and then the field team beneath him. We've got our patient education managers. We'll be building off of what we're doing for WAINUA with AstraZeneca with that team. And all of that will increase some of our SG&A costs, and that is the biggest driver of sort of mid- to high single-digit growth in our OpEx this year. A few thousand patients at most right now. And so what we need in terms of field teams is actually very modest.
We haven't been specific on numbers of field team members yet, but you can imagine that we know where those patients are. They're treated by a select number of physicians, so we'll be able to target them very efficiently. And we'll use other marketing, social, and digital routes to be able to access these physicians and the patients as well. So very efficient, modest sales and marketing effort and medical effort to get to these patients.
And then I think as we scale up to SHTG, obviously, that's a much larger population. So once the drug's approved for SHTG, then we'll basically expand all of those functions appropriately.
Sure. And you're going to think about pricing very differently, obviously, for SHTG, so probably it's fair to assume that the price will come down as you move from FCS to severe hypertriglyceridemia. Maybe a last one question here on Angelman. Two-part question, if I may. One, what was your read of the Ultragenyx data that we actually saw a couple of weeks back? And two, can you tell us how we should be thinking about the data in mid-2024? Are you going to show us only EEG, or are you going to show us EEG as well as function? If you are showing function, what endpoint are you going to show us? And the list goes on, but let me pause there. Any thoughts there? Let me wait on that.
Sure. Yeah. Yeah. So chomping at the bit.
You bet. We probably spend a lot of time talking about somebody else's data, but I'd probably want to focus on ours. I think the difficulty with Angelman Syndrome is that it is a disease that doesn't have a defined regulatory path. So there's a lot of investigations out there. What's going to be the best way to treat this? If you're seeing something, what are the best measures to see it? And all of that is being done to look at a broad range of measures. So it's difficult to say in this early stage with open-label studies, how do you compare this to that? It's really difficult right now, right? But what I can say, what we're doing is looking at all these different measures. A lot of them have been out there for a while. So Bayley-4 is a well-established objective measure.
AS-CGI is a well-established subjective measure. These are things that have been looked at in natural history studies, and we have a pretty good natural history database to compare to. And so when you look at what we're seeing, and we reported this last November at FAST, what we're seeing is that we're seeing a majority of patients showing improvements in those measures in the Bayley-4 and the AS-CGI. And when you look at it compared to natural history, it's different from what you see from natural history. So it looks like there's a signal there, right? And you can't go too much further than that. It's not a placebo-controlled study, so you have to take it with a grain of salt, right? But it's encouraging, right?
And so the next step is basically to then go to regulators and say, "This is the data that we have. How would we suggest designing a phase 3 study to look at this and this as primary endpoints and these as secondary endpoints?" And then you get FDA feedback, and you come to an agreement on how to do the study. And all that is data-centric, so it's all going to be based on what we're seeing in the data, right? As far as what we'll be presenting mid-year, we'll be presenting a lot of that data. So it'll be these subjective and objective measures that you'll see. Initially, we'll likely have a topline readout where we announce at a high level what we're seeing and Biogen's decision on whether or not they license the drug.
And then we'll report more detailed data at a medical conference, which we've already got an idea for where we're going to be presenting that this year. So it won't be very long, and.
Got it. Got it. I have a lot more questions, but no more time. Beth, Wade, thanks so much for joining us. Thanks, everyone, for joining the conversation here. Best of luck for the rest of your conference.
Thank you.
Thank you. It was great to be here.